Combination or Single-Agent Immune Checkpoint Inhibition in MSI-High/dMMR Metastatic Colorectal Cancer?

For patients with microsatellite instability (MSI)-high/mismatch repair protein-deficient (dMMR) metastatic colorectal cancer, first-line treatment with the immune checkpoint inhibitors pembrolizumab or nivolumab is superior to chemotherapy (NEJM JW Oncol Hematol Dec 3 2020 and N Engl J Med 2020; 383:2207). The role of dual-targeted versus single-agent immune checkpoint inhibition in these patients, however, remained an unanswered question.

Investigators now report results of the industry-sponsored, open-label, randomized CheckMate 8HW trial comparing single-agent nivolumab with the combination of ipilimumab and nivolumab. The primary endpoint was progression-free survival (PFS) in patients who had centrally confirmed dMMR/MSI-high metastatic colorectal cancer and were being treated in first or later lines of therapy. Of the 707 patients, 57% had received no prior therapy, 68% had right-sided primary cancers, 14% had confirmed Lynch syndrome, and 82% had central confirmation of MSI-high/dMMR status.

At a median follow-up of 47 months, median PFS was superior with ipilimumab/nivolumab compared with single-agent nivolumab (not reached vs. 39.3 months; hazard ratio, 0.62; P=0.0003). At 36 months, 68% of patients in the combination-therapy arm were free of progression compared with 51% of those in the single-agent nivolumab arm. The response rate was significantly higher with combination therapy than with single-agent nivolumab (71% vs. 58%). No new safety signals were observed.